Advanced therapy medicinal products

Advanced therapy medicinal products (ATMPs) are medicines for human use that are based on genes, tissues or cells. They offer groundbreaking new opportunities for the treatment of disease and injury. ATMPs can be classified into three main types: gene therapy medicines: these contain genes that lead to a therapeutic, prophylactic or diagnostic effect. They work by inserting 'recombinant' genes into the body, usually to treat a variety of diseases, including genetic disorders, cancer or long-term diseases. A recombinant gene is a stretch of DNA that is created in the laboratory, bringing together DNA from different sources; somatic-cell therapy medicines: these contain cells or tissues that have been manipulated to change their biological characteristics or cells or tissues not intended to be used for the same essential functions in the body. They can be used to cure, diagnose or prevent diseases; tissue-engineered medicines: these contain cells or tissues that have been modified so they can be used to repair, regenerate or replace human tissue; In addition, some ATMPs may contain one or more medical devices as an integral part of the medicine, which are referred to as combined ATMPs. An example of this is cells embedded in a biodegradable matrix or scaffold. A Brief History The name of ATMP was introduced by the European Commission Regulation 1394/2007, although medicinal products using either cells or genes were already in development for many years. The development of these products, however, was predominantly an academic affair, based on the field’s advances in molecular editing and culture techniques. The regulatory environment was sharply refocused by the appearance of embryonic stem cells and their potential for manipulation in vitro. The bioethical issues linked to their embryo origin and the in vitro fertilization techniques used for the creation of dedicated embryos raised numerous concerns. In response to these rapid developments in the applied technologies, the European Parliament passed the Regulation 1394/2007 on the proviso that it would enter into force in 2008, and that a subsequent transitory period of three years would be granted for the registration of products already on the market at national level. This estimation of the time required to reach compliance with the centralized Market Authorization process was hugely optimistic and, up to 2017, we still have only six licensed ATMPs, with three of them retired from the market for commercial reasons. In the USA, the FDA Office for Cellular, Tissue and Gene Therapies has granted licenses for seven products which are similar to the European ATMPs (FDA, 2017). A critical development in the field, as usual, would come with new technology. The advent of novel immunotherapies, through the application of the chimeric antigen receptor T-cell gene editing technology was a game-changing event. These new products presented clear market potential by way of outstanding clinical results, which are easier to understand in the regulatory process and a clear mode of action. In fact, the CAR-T-cells can be seen as an evolution of the much-vaunted drug-conjugated antibodies, only with a “drug” that is a living cell. Nevertheless, the long-term viability of these new products needs to be assessed as the business model to be applied is untested with respect to manufacturing and reimbursement. What makes ATMPs different Clinical evidence generation Safety concerns Assessing and paying for value Uncertainty Manufacturing / service delivery Small populations Immune reactions High prices per patient Limited evidence base Can not necessarily be manufactured in bulk No clear comparator Unknown long term effects Greater clinical gains Greater uncertainty increases the cost of wrong decision Short shelf lives Unethical to withhold treatment / use sham therapy Irrecoverable costs Lack of established standards Surrogate outcomes ATMP authorizations and prices In the USA and Europe, the regulation of ATMPs falls under the biologic licensing procedures of the FDA and the European Medicines Agency (EMA), respectively. Both agencies have implemented a regulatory framework to expedite the development and approval of ATMPs that address unmet medical needs or provide new therapies for serious or life?threatening diseases. Both regulatory frameworks also enable the use of technical requirements adapted to the characteristics of each ATMP and explicitly enable companies and other developers to gain access to scientific and regulatory advice from the respective agency. Medical devices intended for use with a specific ATMP may be evaluated either as part of the ATMP or as stand?alone devices. There are differences in the classification of ATMPs by the FDA and the EMA. The FDA classifies hematopoietic progenitor cell (HPC) cord blood products as an AMTP. The EMA considers that HPC cord blood products do not fit the definition of AMTP because they are not subject to substantial manipulation and are intended to be used for the same essential function in the recipient and the donor. As of December 31, 2018, the FDA had authorized 16 ATMPs (11 cell therapies, including eight HPC cord blood products; four gene therapy products and one tissue engineering product), and the EMA had authorized 13 ATMPs (three cell therapies, six gene therapy products, and four tissue engineering products; Table 1). Six products (autologous cultured chondrocytes on a porcine collagen membrane?specific marker proteins, axicabtagene ciloleucel, sipuleucel?T, talimogene laherparepvec, tisagenlecleucel, and voretigene neparvovec) were authorized by both agencies. The FDA and EMA also granted orphan designation to 4 and 8 ATMPs, respectively. These products address several disease areas including progenitor cell transplantation, cancer, and cartilage defects. However, companies had also withdrawn 4 ATMPs authorized by the EMA from the market, citing commercial reasons for discontinuing their availability. Demonstrating biosimilarity for ATMPs While the generics market for drugs, medical devices, and some biologics has been driving down prices and improving affordability and access to medicinal products, the challenge to establish a similar market of generics makers of ATMPs is considerably greater. A first barrier would be the current regulatory scheme itself. ATMP is a complex and dynamic regulatory area compared with the now well?established regulation of drugs, biologics, and medical devices. Products classified under the ATMP umbrella can be very diverse, and current regulations are product?specific and focus on incentivizing innovation. It would first require a stable and well?defined ATMP regulatory framework that sets reference standards and criteria for approval, along with implementing regulatory pathways for ATMP biosimilar review and authorization. The demonstration of biosimilarity for ATMPs is also challenging because those products are often complex active substances, patient?specific (autologous), or require careful matching of donor and recipient (allogeneic). Moreover, only few validated biomarkers for establishing biosimilarity have been identified. Regulatory systems must address the complexity of ATMPs and the difficulty of comparing outcomes and demonstrating biosimilarity of highly individualized therapies to ensure clinical equivalence. The development of biosimilar ATMPs will also depend on the cost and barriers to access the innovator product, which is required to perform comparative studies. In addition, biosimilar ATMP clinical studies—if required—will be challenging and costly and face the same difficulties in enrolling sufficient number of patients as the original product. The success of a ATMP biosimilar industry will also require the development of technologies to enable large?scale, reproducible, and cost?effective manufacturing of high?quality products (Dwarshuis et al, 2017). Lastly, while the current regulatory framework for ATMPs focuses on providing companies with incentives for innovation, it is not necessarily supporting competition. Aligning the necessary incentives for research and development with health care budgetary constraints is an important challenge for policymakers and regulatory agencies (Rodriguez?Monguio et al, 2017). Yet, the complexities of the regulatory framework, clinical effectiveness, and safety, along with the economic and ethical issues of ATMP innovation, access, and affordability, have not been sufficiently discussed so far. References: https://www.ema.europa.eu/en/human-regulatory/overview/advanced-therapy-medicinal-products-overview https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622199/ https://ec.europa.eu/health/human-use/advanced-therapies_en http://www.ich.org/fileadmin/Public_Web_Site/Training/ASEAN_Q5C_workshop_May_2011/SESSION_IVb_ATMPs.pdf By Afandiyev R.